Everolimus (RAD-001) (FIG. 1) is an immunosuppressant semi-synthetic drug, marketed by Novartis under the trade names of Zortress® (USA) and Certican® (Europe and other countries) as transplantation medicine and as Afinitor® in oncology. Everolimus is a derivative of Sirolimus (Rapamycin), works similarly to Sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is mainly used as an immunosuppressant to prevent rejection in organ transplantation. Everolimus is also used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Structurally, Everolimus is 40-O-(2-Hydroxy)ethyl rapamycin. FDA has approved Everolimus in March 2009 for the treatment of advanced kidney cancer, and for the organ rejection prophylaxis in April 2010.
The structure and synthesis of Everolimus [40-O-(2-Hydroxy)ethyl rapamycin] and its use as an immunosuppressant was first described in U.S. Pat. No. 5,665,772 along with other novel Rapamycin derivatives. For the synthesis, firstly Ramapycin and 2-(t-butyldimethylsilyl)oxyethyl triflate are reacted in presence of 2,6-Lutidine in toluene at around 60° C. to obtain corresponding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin, which then converted into Everolimus [40-O-(2-Hydroxy)ethyl rapamycin]. However, the conversion resulted in very poor overall yield.
U.S. Pat. No. 7,297,703 B2 disclosed the use of antioxidant such as 2,6-di-tert-butyl-4-methylphenol for improving the stability of poly-ene macrolides. U.S. Pat. No. 7,297,703 B2 also disclosed substantially pure crystalline polymorph of Everolimus having m.p. 146.5° C. For that amorphous Everolimus is converted into the crystalline form using ethyl acetate and heptane solvents. It is also mentioned that the crystalline form is non-solvate form.